The therapeutic potential of stem cells in heart disease

Abstract.  Coronary heart disease and chronic heart failure are common and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impairs quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies within the past few years have been demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukaemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non-ischemic cardiomyopathy (dilative cardiomyopathy) and heart failure due to hypertensive heart disease.     

The role of stem cells in cardiac regeneration

After myocardial infarction, injured cardiomyocytes are replaced by fibrotic tissue promoting the development of heart failure. Cell transplantation has emerged as a potential therapy and stem cells may be an important and powerful cellular source. Embryonic stem cells can differentiate into true cardiomyocytes, making them in principle an unlimited source of transplantable cells for cardiac repair, although immunological and ethical constraints exist. Somatic stem cells are an attractive option to explore for transplantation as they are autologous, but their differentiation potential is more restricted than embryonic stem cells. Currently, the major sources of somatic cells used for basic research and in clinical trials originate from the bone marrow. The differentiation capacity of different populations of bone marrow-derived stem cells into cardiomyocytes has been studied intensively. The results are rather confusing and difficult to compare, since different isolation and identification methods have been used to determine the cell population studied. To date, only mesenchymal stem cells seem to form cardiomyocytes, and only a small percentage of this population will do so in vitro or in vivo. A newly identified cell population isolated from cardiac tissue, called cardiac progenitor cells, holds great potential for cardiac regeneration. Here we discuss the potential of the different cell populations and their usefulness in stem cell based therapy to repair the damaged heart.     

Cell transplantation in heart failure management

Heart failure is becoming a major issue for public health in western countries and the effect of currently available therapies is limited. Therefore cell transplantation was developed as an alternative strategy to improve cardiac structure and function. This review describes the multiple cell types and clinical trials considered for use in this indication. Most studies have been developed in models of post-ischemic heart failure. The transplantation of fetal or neonatal cardiomyocytes has proven to be functionally successful, but ethical as well as immunological and technical reasons make their clinical use limited. Recent reports, however, suggested that adult autologous cardiomyocytes could be prepared from stem cells present in various tissues (bone marrow, vessels, adult heart itself, adipose tissue). Alternatively, endothelial progenitors originating from bone marrow or peripheral blood could promote the neoangiogenesis within the scar tissue. Hematopietic stem cells prepared from bone marrow or peripheral blood have been proposed but their differentiation ability seems limited. Finally, the transplantation of skeletal muscle cells (myoblasts) in the infarcted area improved myocardial function, in correlation with the development of skeletal muscle tissue in various animal models. The latter results paved the way for the development of a first phase I clinical trial of myoblast transplantation in patients with severe post-ischemic heart failure. It required the scale-up of human cell production according to good manufacturing procedures, started in june 2000 in Paris and was terminated in november 2001, and was followed by several others. The results were encouraging and prompted the onset of a blinded, multicentric phase II clinical trial for skeletal muscle cells transplantation. Meanwhile, phase I clinical trials also evaluate the safeness and efficacy of various cell types originating from the bone marrow or the peripheral blood. However, potential side effects related to the biological properties of the cells or the delivery procedures are being reported. High quality clinical trials supported by strong pre-clinical data will help to evaluate the role of cell therapy as a potential treatment for heart failure.     

c-kit~+心脏干细胞在心脏再生修复中的应用

心血管疾病的流行是一个全球性的现象,在我国,其患病率也不断增长。目前尚无有效的治疗方法以解决心肌细胞损失这一关键问题,而干细胞移植很可能成为新的治疗方法。C-kit+心脏干细胞(cardiac stem/progenitor cell,CSCs)的发现证实了CSCs的存在,并为心脏的再生和修复治疗带来了新的曙光。C-kit+CSCs在心肌梗死、心力衰竭等心脏疾病中的作用得到了多项体内外实验及临床试验的证实,但由于目前尚缺乏直接的充分的证据证明内源性或外源性的c-kit+CSCs可分化为相当数量的成熟的具有功能的心肌细胞,其治疗机制尚存争议,同时,将其应用于临床仍面临多个问题。     

Cellular therapy in cardiology

Cardiac cell therapy has been initially designed to regenerate the infarcted myocardium through its repopulation by new cells able to restore function of scar areas. Six years after the first human application of this novel approach, it is timely appropriate to review the results of the first randomised trials in the three major indications, i.e., acute myocardial infarction, heart failure, and refractory angina. It should be recognized that the results are mixed, with benefits ranging from absent to transient and, at most, marginal. However, lessons drawn from this first wave of clinical series and the experimental data that have been concomitantly collected are multiple and highly informative. They indicate that adult stem cells, whether muscular or bone marrow-derived, fail to generate new cardiomyocytes. They suggest that the potential benefits of cardiac cell therapy are thus mediated by alternate mechanisms such as limitation of left ventricular remodelling or paracrine activation of signalling pathways involved in angiogenesis. They highlight the fact that the therapeutic benefits of grafted cells will not be fully exploited until issues of cell transfer and postengraftment survival have not been adequately addressed. These observations thus allow us to better fine-tune upcoming research, which should specifically concentrate on the development of cells featuring a true regeneration potential. In this setting, the greatest promises are currently held by embryonic stem cells.     

Cell therapy for ischaemic heart disease: focus on the role of resident cardiac stem cells

Myocardial infarction results in loss of cardiomyocytes, scar formation, ventricular remodelling, and eventually heart failure. In recent years, cell therapy has emerged as a potential new strategy for patients with ischaemic heart disease. This includes embryonic and bone marrow derived stem cells. Recent clinical studies showed ostensibly conflicting results of intracoronary infusion of autologous bone marrow derived stem cells in patients with acute or chronic myocardial infarction. Anyway, these results have stimulated additional clinical and pre-clinical studies to further enhance the beneficial effects of stem cell therapy. Recently, the existence of cardiac stem cells that reside in the heart itself was demonstrated. Their discovery has sparked intense hope for myocardial regeneration with cells that are obtained from the heart itself and are thereby inherently programmed to reconstitute cardiac tissue. These cells can be detected by several surface markers (e.g. c-kit, Sca-1, MDR1, Isl-1). Both in vitro and in vivo differentiation into cardiomyocytes, endothelial cells and vascular smooth muscle cells has been demonstrated, and animal studies showed promising results on improvement of left ventricular function. This review will discuss current views regarding the feasibility of cardiac repair, and focus on the potential role of the resident cardiac stem and progenitor cells. (Neth Heart J 2009;17:199–207.)     

Cell transplantation for cardiac regeneration: where do we stand?

During the last decade transplantation of cells into the heart has emerged as a novel therapy for the prevention and treatment of heart failure. Although various cell types have been used, most experience has been obtained with the progenitor cells of skeletal muscle, also called myoblasts, and a wide array of bone marrow-derived cell types. The first preclinical studies demonstrated an improvement in global and regional heart function that was attributed mainly to a direct contractile effect of the transplanted cells. Furthermore, it was suggested that multiple cell types are able to form true cardiomyocytes and truly ‘regenerate’ the myocardium. More recent studies have questioned these early findings. Other mechanisms such as paracrine effects on the infarct and remote myocardium, a reduction in adverse remodelling and improvement of mechanical properties of the infarct tissue likely play a more important role. On the basis of encouraging preclinical studies, multiple early-phase clinical trials and several randomised controlled trials have been conducted that have demonstrated the feasibility, safety and potential efficacy of this novel therapy in humans. This review summarises the available evidence on cardiac cell transplantation and provides an outlook on future preclinical and clinical research that has to fill in the remaining gaps. (Neth Heart J 2008; 16:88-95.)     

Growth and differentiation of human embryonic stem cells for cardiac cell replacement therapy

Due to the limited proliferation capacity of cardiac cells, cell replacement therapy has been proposed to restore cardiac function in patients suffering from ischemic heart disease and congestive heart failure. However, this approach is challenged by an insufficient supply of appropriate cells. Because of their apparent indefinite replicative capacity and their cardiac differentiation potential, human embryonic stem cells (hESCs) are potential candidates as sources of cells for cell replacement therapy. Significant progress has been made in improving culture conditions of undifferentiated hESCs, and using various methods, several laboratories have reported the generation of contracting cardiomyocytes from hESCs in vitro. Application of these cardiomyocytes to the clinic, however, still requires substantial experimentation to show that 1) they are functional in vitro; 2) they are efficacious in animal models of cardiac injury and disease; 3) they are safe and effective in human conditions, and 4) a sufficient amount of cardiomyocytes with expected characteristics can be generated in a reproducible manner. Here we review and discuss current findings on growth and differentiation of hESCs, and on characterization, enrichment and transplantation of hESC-derived cardiomyocytes.     

Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium

Neovascularization induced by vascular endothelial growth factor (VEGF) represents an appealing approach for treating ischemic heart disease. However, VEGF therapy has been associated with transient therapeutic effects and potential risk for hemangioma growth. Adult mesenchymal stem cells (MSCs) derived from bone marrow are a promising source for tissue regeneration and repair. In order to achieve a safe and persistent angiogenic effect, we have explored the potential of autologous MSCs transplantation to enhance angiogenesis and cardiac function of ischemic hearts. One week after myocardial infarction induced by occlusion of left anterior descending artery, autologous MSCs expanded in vitro was administrated intramyocardially into the infarct area of the same donor rats. By 2 months, MSCs implantation significantly elevated VEGF expression levels, accompanied by increased vascular density and regional blood flow in the infarct zone. The neovascularization resulted in a decreased apoptosis of hypertrophied myocytes and markedly improved the left ventricular contractility (ejection fraction: 79.9+/-7.6% vs. 37.2+/-6.9% in control animals). Therefore, mechanisms underlying MSCs improvement of cardiac functions may involve neovascularization induced by differentiation of MSCs to endothelial cells and para-secretion of growth factors, in addition to the apoptosis reduction and previously reported cardiomyocytes regeneration. Two months after cell transplantation, there are significant improvement of left ventricular function. Hence, autologous MSCs transplantation may represent a promising therapeutic strategy free of ethical concerns and immune rejection, for neovascularization in ischemic heart diseases.     

Hepatic tissue engineering: from transplantation to customized cell-based liver directed therapies from the laboratory

Today, liver transplantation is still the only curative treatment for liver failure due to end-stages liver diseases. Donor organ shortage, high cost and the need of immunosuppressive medications are still the major limitations in the field of liver transplantation. Thus, alternative innovative cell-based liver directed therapies, e.g. liver tissue engineering, are under investigation with the aim, that in future an artificial liver tissue could be created and be used for the replacement of the liver function in patients. Using cells instead of organs in this setting should permit (i) expansion of cells in an in vitro phase, (ii) genetic or immunological manipulation of cells for transplantation, (iii) tissue typing and cryopreservation in a cell bank, and (iv) the ex vivo genetic modification of patient's own cells prior re-implantation. Function and differentiation of liver cells are influenced by the three-dimensional organ architecture. The use of polymeric matrices permits the three dimensional formation of a neo-tissue and specific stimulation by adequate modification of the matrix-surface which might be essential for appropriate differentiation of transplanted cells. Additionally, culturing hepatocytes on three dimensional matrices permits culture in a flow bioreactor system with increased function and survival of the cultured cells. Based on bioreactor technology, bioartificial liver devices (BAL) are developed for extracorporeal liver support. Although BALs improved clinical and metabolic conditions, increased patient survival rates have not been proven yet. For intra-corporeal liver replacement, a concept which combines Tissue Engineering using three-dimensional, highly porous matrices with cell transplantation could be useful. In such a concept, whole liver mass transplantation, long term engraftment and function as well as correction of a metabolic defect in animal models could be achieved with a principally reversible procedure. Future studies have to investigate, which environmental conditions and transplantation system would be most suitable for the development of artificial functional liver tissue including blood supply for a potential use in a clinical setting.     

The influence of cardiovascular risk factors on bone marrow mesenchymal stromal cell fitness

Background aimsIn the past, cell transplantation strategies for the treatment of heart failure have shown promising results in experimental and clinical studies. Bone marrow (BM)-derived stem cells represent the most frequently used cell population. Within this heterogeneous cell population, mesenchymal stromal cells (MSC) have been identified to induce therapeutic effects, mainly through paracrine mechanisms. Because of their low frequency in native tissues, in vitro cell culture expansion is mandatory prior to transplantation. We sought to identify patient-specific cardiovascular risk factors influencing the proliferative potential of MSC.MethodsBM aspirates from 51 patients undergoing elective cardiac surgery were analyzed for MSC frequency and cell culture expansion potential. Fibroblastic colony-forming units (CFU-F) were quantified for culture conditions applying autologous (AS) or fetal bovine serum (FBS) and different basic media. Univariate and multivariate analyzes were performed in order to determine the impact of patient-specific factors on CFU-F numbers.ResultsExpanded MSC showed a specific immune phenotype and displayed adipogenic, chondrogeneic and osteogeneic differentiation potential. CFU-F numbers did not differ under AS or FBS supplementation. Elevated numbers of mononuclear cells, diabetes mellitus, steroid treatment, chronic obstructive pulmonary disease, renal failure, high euroSCORE and impaired left ventricular function were significant determinants for higher CFU-F numbers.ConclusionsThe impact of specific cardiovascular risk factors on MSC fitness could be determined. These results may help to establish patient profiling in order to identify patients suitable for autologous MSC transplantation, and might lead to the identification of disease-related mechanisms of stem cell activation.     

Local activation of cardiac stem cells for post‐myocardial infarction cardiac repair

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue‐specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time‐consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC‐based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post‐MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC‐based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.     

Stem cell therapy for heart failure:Medical breakthrough,or dead end?

Heart failure continues to be one of the leading causes of morbidity and mortality worldwide.Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue.Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology.Heart transplantation usually cannot be relied on,as there is a major discrepancy between the availability of donors and recipients.As a result,heart failure carries a poor prognosis and high mortality rate.As the heart lacks significant endogenous regeneration potential,novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues.This review will discuss past,present,and future clinical trials,factors that influence stem cell therapy outcomes as well as ethical and safety considerations.Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function.This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type,dosing,route of administration,patient parameters and other important variables that contribute to successful stem cell therapy.Nonetheless,the field of stem cell therapeutics continues to advance at an unprecedented pace.We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.     

Stem cell engineering for treatment of heart diseases: Potentials and challenges

Heart disorders are a major health concern worldwide responsible for millions of deaths every year. Among the many disorders of the heart, myocardial infarction, which can lead to the development of congestive heart failure, arrhythmias, or even death, has the most severe social and economic ramifications. Lack of sufficient available donor hearts for heart transplantation, the only currently viable treatment for heart failure other than medical management options (ACE inhibition, beta blockade, use of AICDs, etc.) that improve the survival of patients with heart failure emphasises the need for alternative therapies. One promising alternative replaces cardiac muscle damaged by myocardial infarction with new contractile cardiomyocytes and vessels obtained through stem cell-based regeneration.We report on the state of the art of recovery of cardiac functions by using stem cell engineering. Current research focuses on (a) inducing stem cells into becoming cardiac cells before or after injection into a host, (b) growing replacement heart tissue in vitro, and (c) stimulating the proliferation of the post-mitotic cardiomyocytes in situ. The most promising treatment option for patients is the engineering of new heart tissue that can be implanted into damaged areas. Engineering of cardiac tissue currently employs the use of co-culture of stem cells with scaffold microenvironments engineered to improve tissue survival and enhance differentiation. Growth of heart tissue in vitro using scaffolds, soluble collagen, and cell sheets has unique advantages. To compensate for the loss of ventricular mass and contractility of the injured cardiomyocytes, different stem cell populations have been extensively studied as potential sources of new cells to ameliorate the injured myocardium and eventually restore cardiac function. Unresolved issues including insufficient cell generation survival, growth, and differentiation have led to mixed results in preclinical and clinical studies. Addressing these limitations should ensure the successful production of replacement heart tissue to benefit cardiac patients.     

Central zone of myocardial infarction: a neglected target area for heart cell therapy

The purpose of this study was to investigate the fate of transplanted cells in the central zone of myocardial infarction (MI), and to clarify the relationship between the injection-site impact and the efficacy of cell therapy. MI was created by coronary ligation in female rats. Three weeks later, 3-million labelled male bone marrow mesenchymal stem cells (BMSCs) were directly injected into the border (BZC group) or central zone (CZC group) of MI area. As a control, culture medium was injected into the same sites. Cell survival was evaluated by quantitative real-time polymerase chain reaction, and apoptosis was assayed with TUNEL and caspase-3 staining. Four weeks after transplantation, heart function and cardiac morphometry were evaluated by echocardiography and Masson's Trichrome staining, respectively. Angiogenesis and myogenesis were detected by immunofluorescence staining. After cell transplantation into the border or central zone, there was no cell migration between the different zones of MI. BMSCs in the CZC group exhibited no difference in apoptotic percentage, in the long-term survival, when compared with those in the BZC group. However, they did effectively promote angiogenesis and cellular myogenic differentiation. Although cell delivery in the central zone of MI had no effect on the recovery of heart function compared with the BZC group, the retained BMSCs could still increase the scar thickness, and subsequently exhibit a trend in the reverse remodelling of ventricular dilation. Hence, we concluded that the central zone of MI should not be ignored during cell-based therapy. Multiple site injection (border+central zone) is strongly recommended during the procedure of cell transplantation.     

Progenitor cell therapy for heart disease

Many cell types are currently being studied as potential sources of cardiomyocytes for cell transplantation therapy to repair and regenerate damaged myocardium. The question remains as to which progenitor cell represents the best candidate. Bone marrow-derived cells and endothelial progenitor cells have been tested in clinical studies. These cells are safe, but their cardiogenic potential is controversial. The functional benefits observed are probably due to enhanced angiogenesis, reduced ventricular remodeling, or to cytokine-mediated effects that promote the survival of endogenous cells. Human embryonic stem cells represent an unlimited source of cardiomyocytes due to their great differentiation potential, but each step of differentiation must be tightly controlled due to the high risk of teratoma formation. These cells, however, confront ethical barriers and there is a risk of graft rejection. These last two problems can be avoided by using induced pluripotent stem cells (iPS), which can be autologously derived, but the high risk of teratoma formation remains. Cardiac progenitor cells have the advantage of being cardiac committed, but important questions remain unanswered, such as what is the best marker to identify and isolate these cells? To date the different markers used to identify adult cardiac progenitor cells also recognize progenitor cells that are outside the heart. Thus, it cannot be determined whether the cardiac progenitor cells identified in the adult heart represent resident cells present since fetal life or extracardiac cells that colonized the heart after cardiac injury. Developmental studies have identified markers of multipotent progenitors, but it is unknown whether these markers are specific for adult progenitors when expressed in the adult myocardium. Cardiac regeneration is dependent on the stability of the cells transplanted into the host myocardium and on the electromechanical coupling with the endogenous cells. Finally, the promotion of endogenous regenerative processes by mobilizing endogenous progenitors represents a complementary approach to cell transplantation therapy.     

Arrhythmogenic risks of stem cell replacement therapy for cardiovascular diseases

Ischemic heart disease and congestive heart failure are major contributors to high morbidity and mortality. Approximately 1.5 million cases of myocardial infarction occur annually in the United States; the yearly incidence rate is approximately 600 cases per 100,000 people. Although significant progress to improve the survival rate has been made by medications and implantable medical devices, damaged cardiomyocytes are unable to be recovered by current treatment strategies. After almost two decades of research, stem cell therapy has become a very promising approach to generate new cardiomyocytes and enhance the function of the heart. Along with clinical trials with stem cells conducted in cardiac regeneration, concerns regarding safety and potential risks have emerged. One of the contentious issues is the electrical dysfunctions of cardiomyocytes and cardiac arrhythmia after stem cell therapy. In this review, we focus on the cell sources currently used for stem cell therapy and discuss related arrhythmogenic risk.     

胚胎干细胞的心脏应用

心肌梗死期间死亡的心肌细胞将由没有收缩功能的疤痕组织替代,因而极可能引起心力衰竭。对治疗心衰来说,修复死亡或损伤的心肌以及改善心功能仍面临着极大挑战。干细胞移植已在近年来的实验中用于修复损失的心肌。本文总结了近期在心肌损伤动物中实施胚胎干细胞移植的实验结果,并着重介绍对这类特定细胞的研究进展。胚胎干细胞取源于早期哺乳类胚胎的胚芽细胞,属于多功能干细胞。这类细胞具有长期增殖而不分化的能力,或台色够在培养过程中分化成包括心肌细胞在内的所有特殊体细胞。由于胚胎干细胞具有极大的增殖和分化为成熟组织的能力,它们可能成为一种潜在的很有实用价值的细胞来源,可用于对病态心脏的功能心肌再生的细胞治疗。新近的研究表明,在心肌梗死动物模型中,心肌内移植胚胎干细胞或由其分化成的心肌样细胞,能导致已损伤心肌的再生,并改善心脏功能。另外,在病毒性心肌炎小鼠中,静脉输入胚胎干细胞可明显提高生存率和减轻心肌损伤。有关人类胚胎干细胞在体外分化成心肌细胞以及这些细胞的特性,近来已有报道。然而,要在临床能应用人类胚胎干细胞或由其分化成的心肌细胞来治疗晚期心脏疾病,还必须越过大量的伦理、法律和科学上的障碍。     

Adult stem cells for cardiac repair: a choice between skeletal myoblasts and bone marrow stem cells

The real promise of a stem cell-based approach for cardiac regeneration and repair lies in the promotion of myogenesis and angiogenesis at the site of the cell graft to achieve both structural and functional benefits. Despite all of the progress and promise in this field, many unanswered questions remain; the answers to these questions will provide the much-needed breakthrough to harness the real benefits of cell therapy for the heart in the clinical perspective. One of the major issues is the choice of donor cell type for transplantation. Multiple cell types with varying potentials have been assessed for their ability to repopulate the infarcted myocardium; however, only the adult stem cells, that is, skeletal myoblasts (SkM) and bone marrow-derived stem cells (BMC), have been translated from the laboratory bench to clinical use. Which of these two cell types will provide the best option for clinical application in heart cell therapy remains arguable. With results pouring in from the long-term follow-ups of previously conducted phase I clinical studies, and with the onset of phase II clinical trials involving larger population of patients, transplantation of stem cells as a sole therapy without an adjunct conventional revascularization procedure will provide a deeper insight into the effectiveness of this approach. The present article discusses the pros and cons of using SkM and BMC individually or in combination for cardiac repair, and critically analyzes the progress made with each cell type.     

Cardiomyocyte progenitor cell‐derived exosomes stimulate migration of endothelial cells

Patients suffering from heart failure as a result of myocardial infarction are in need of heart transplantation. Unfortunately the number of donor hearts is very low and therefore new therapies are subject of investigation. Cell transplantation therapy upon myocardial infarction is a very promising strategy to replace the dead myocardium with viable cardiomyocytes, smooth muscle cells and endothelial cells, thereby reducing scarring and improving cardiac performance. Despite promising results, resulting in reduced infarct size and improved cardiac function on short term, only a few cells survive the ischemic milieu and are retained in the heart, thereby minimizing long-term effects. Although new capillaries and cardiomyocytes are formed around the infarcted area, only a small percentage of the transplanted cells can be detected months after myocardial infarction. This suggests the stimulation of an endogenous regenerative capacity of the heart upon cell transplantation, resulting from release of growth factor, cytokine and other paracrine molecules by the progenitor cells – the so-called paracrine hypothesis. Here, we focus on a relative new component of paracrine signalling, i.e. exosomes. We are interested in the release and function of exosomes derived from cardiac progenitor cells and studied their effects on the migratory capacity of endothelial cells.